Anticonvulsant toxicity

Carbamazepine

• Predictable dose-dependent CNS depression and anticholinergic effects
• Risk assessment
  • 20-50mg/kg: Mild to moderate CNS depression and anticholinergic effects
  • >50mg/kg: Fluctuating mental status, agitated delirium and risk of coma within first 12 hours. Risk of hypotension and cardiotoxicity in extreme doses
  • If larger overdoses, anticholinergic effects may be prominent prior to coma
  • Coma then is expected to last for days due to ongoing absorption, pharmacobezoar formation, slow elimination and active metabolites
  • Pregnancy: Teratogenic so first-trimester OD warrants further antenatal assessment
  • Children: Single 400mg tablet potentially intoxicating and any dose >400mg warrants observation for at least 8 hours

Carbamazepine

• Toxic mechanism:
  • Structurally similar to TCA imipramine
  • Inhibits inactivated sodium channels, preventing further action potentials
  • Blocks NA reuptake and antagonist at muscarinic, nicotinic and NMDA receptors
• Toxicokinetics
  • Slowly and erratically absorbed
  • Ileus secondary to anticholinergic effects prolongs this further
  • Small Vd
  • Hepatic metabolism CytP450 3A4 to active metabolite, which is then inactivated and excreted in urine
  • Induces its own metabolism in chronic use – Important to know this
    • Occurs early in use, is dose-dependent
    • Explains why naïve patients suffer more toxic effects at same dose than chronic users

Carbamazepine

• Clinical features
  • Usually evident by 4 hours but can peak at 8-12 hours (particularly CR)
  • Fluctuating absorption and clinical course is typical
    • Medication clumping and slow dissolution may occur with standard and SR preparations
  • Mild-moderate CNS: Nystagmus, dysarthria, ataxia, sedation, delirium, mydriasis, ophthalmoplegia and myoclonus
  • Anticholinergic: Urinary retention, tachycardia, dry mouth (esp. early on)
  • Coma can be delayed to 8-12 hours
  • Large overdoses may lead to seizures hypotension, ventricular dysrhythmias

Carbamazepine

• Investigations
  • Serum CBZ levels confirm diagnosis
  • Single test if mild-moderate but repeated q6h if in coma to monitor course
  • If SR preparation, peak serum concentrations can be delayed up to 4 days
  • Levels
    • 8-12mcg/L therapeutic
    • >12mcg/L nystagmus and ataxia
    • >20mcg/L CNS and anticholinergic effects
    • >40mcg/L Coma, seizures and cardiac conduction abnormalities
  • Serial 12-lead ECG every 12 hours for sodium-channel blockade (1^st degree AV block and broad QRS)

Carbamazepine

• Supportive care
• Treat ventricular dysrhythmias with bicarb as for TCA
• Seizures and agitated delirium – Benzos
• Decontamination
  • Activated charcoal for ingestions <50mg/kg or larger ingestions of controlled-release that present very early and well
    • If CNS toxicity at all evident, only administer AC once intubated
  • WBI in large overdoses of SR preparations
• Enhanced elimination
  • MAC for intubated patients 25g q2h with bowel sounds and not high aspirates
  • Haemodialysis indicated in prolonged coma with levels >40 after 48 hours or ongoing haemodynamic instability

Carbamazepine

• Disposition
  • Children >20mg/kg observe at least 8 hours and overnight
  • If well after 8 hours, discharge
  • If ongoing mild-moderate CNS, observe 8 hours in ED then can admit to ward
• Handy tips
  • In suspected paediatric ingestion, an undetectable CBZ level any time after first hour excludes ingestion and allows immediate discharge
• Pitfalls
  • Failure to appreciate potential for delayed toxicity
  • Failure to detect urinary retention

Phenytoin

• Usually benign with dose-dependent ataxia and CNS depression
• Falls are the greatest danger
• Risk assessment
  • Dose-dependent CNS effects (mainly cerebellar) after acute ingestion
    • 10-15mg/kg: Standard therapeutic loading dose
    • >20mg/kg: Ataxia, dysarthria, nystagmus
    • >100mg/kg: Potential for coma and seizures
  • Coma and seizures rare even with massive OD
  • Cardiovascular effects only seen after rapid IV infusion (due to propylene glycol)
  • Children: One or two 100mg tablets enough to cause symptoms but only need observation at home unless deteriorate

Phenytoin

• Toxic mechanism:
  • Sodium channel blocker to suppress membrane excitability
• Toxicokinetics
  • Absorption slow and erratic. Peak serum levels 24-48 hours
  • Vd low and highly protein bound
  • Metabolism: Hepatic hydroxylation (cytP450 2c9) to inactive metabolite
  • Saturable (Michaelis-Menten kinetics) and plasma levels and half-life rise dramatically with small increase in daily dose
  • Elimination half-life in poisoning is 24-230 hours

Phenytoin

• Clinical features
  • Chronic toxicity: ataxia, dysarthria and nystagmus commonly
  • Acute toxicity
    • Mild GI upset within 2 hours
    • Slowly over hours develop slow horizontal nystagmus, dysarthria, tremor, vertical nystagmus, drowsiness, involuntary movements and ophthalmoplegia
    • Typically resolves over 2-4 days
    • Massive ingestion can cause coma, rigidity, seizures, hypernatraemia, hyperglycaemia and non-ketotic hyperosmolar state
    • Permanent cerebellar injury rare after prolonged severe OD

Phenytoin

• Handy tips
  • Consider phenytoin OD if on chronic therapy and have difficulty walking
  • Coma is rare so always consider other causes
• Pitfalls
  • Failure to order a phenytoin level on a patient on it chronically who presents with ataxia or non-specific symptoms
  • Allowing unsupervised ambulation

Valproic acid

• Most result in CNS depression
• Large overdoses can cause MODS and death
• Death preventable with early haemodialysis
• Chronic valproate toxicity is associated with life-threatening idiosyncratic hyperammonaemia and hepatotoxicity

Valproate

• Risk assessment
  • Dose-dependent CNS depression can be delayed up to 12 hours
  • <200mg/kg: Asymptomatic or mild drowsiness/ataxia
  • 200-400mg/kg: Variable CNS depression. Airway control rare
  • 400-1000mg/kg: Significant CNS depression, coma (delayed up to 12 hours)
  • >1000mg/kg: Profound prolonged coma, multiorgan toxicity, cerebral oedema, hypotension, lactic acidosis, hypoglycaemia, hyperammonaemia, hypernatraemia, hypocalcaemia and bone marrow suppression
  • Ingestion >1g/kg is potentially lethal
  • Children: <200mg/kg observe at home

Valproate

• Toxic mechanism
  • Increases levels of GABA and inhibits mitochondrial pathways in high concentrations
• Toxicokinetics
  • Usually well absorbed but can be slow and erratic in massive OD
  • Peak levels delayed up to 18 hours
  • Highly protein bound and small Vd
  • Hepatic metabolism to multiple active metabolites
  • In overdose, hepatic L-carnitine stores can be depleted shifting metabolism towards more toxic oxidative pathways (akin to paracetamol)

Valproate

• Clinical features
  • Usually presents asymptomatic even in massive OD
  • Progressive deterioration in conscious state with rising levels
  • In severe poisoning, coma and toxicity can persist for days after levels return to normal
• Serial levels
  • Confirm poisoning, refine risk assessment and guide therapy
  • Should be taken if >100mg/kg then q6h until peaked and falling
  • Levels correlate well with degree of CNS depression and risk of systemic toxicity

Valproate

• Serum levels
  • <3500micromol/L (<500mg/L): Not usually MODS
  • >3500micromol/L (>500mg/L): Usually coma
  • >7000micromol/L (>1000mg/L): Life-threatening MODS
  • >14 000 micromol/L (> 2000mg/L): Death without urgent haemodialysis
• If CNS depression or ingestion >400mg/kg, repeat every 4-6 hours until decreasing
• In comatose patient, levels dictate need for haemodialysis

Valproate

• Management
  • Supportive care
  • Intubate early if declining level of consciousness
• Decontamination
  • AC not indicated if <400mg/kg
  • Repeat dose at 3-4 hours may reduce absorption and peak levels and is recommended in intubated patients with bowel sounds and rising levels
  • Remember AC only 10:1 adsorption
  • WBI if >1g/kg of sustained release preparations

Newer agents

• Gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin
• Far less toxic than older agents
• Risk assessment
  • Mild and transient CNS depression with non-specific symptoms
  • Usually symptoms arise within 2 hours and resolve within 24
  • Coma and seizures are rare
  • Children: Benign and hospital assessment only required if symptomatic

Newer agents

• Toxic mechanism
  • Mostly GABA augmentation (enhancing GABA release or inhibiting reuptake)
  • Lamotrigine and topiramate also have voltage-dependent Na-channel effects
  • Topiramate also inhibits carbonic anhydrase
  • Pregabalin prevents release of glutamate by blocking calcium channels
• Toxicokinetics
  • All well absorbed orally
  • Mostly hepatic metabolism to inactive metabolites
  • Levetiracetam, pregabalin and topiramate are all excreted unchanged in urine
  • Absorption of gabapentin from GI is saturable and may help limit toxicity in overdose

Newer agents

• Clinical features
  • Gabapentin: Nausea, vomiting, hypotension, drowsiness. Resolves within 10 hrs
  • Levetiracetam: Agitation, reduced LOC, coma, respiratory depression
  • Oxcarbazepine: Sedation (mild)
  • Pregabalin: Drowsiness only
  • Tiagabine: Sedation, coma, respiratory depression and seizures
  • Topiramate: Ataxia, sedation coma, seizures, hypotension and metabolic acidosis
    • NAGMA due to carbonic anhydase inhibition can persist for 7 days
  • Vigabatrin: Drowsiness and delirium

Newer agents

Newer agents

• Supportive care
• Benzos for seizures
• Decontamination
  • Routine AC not beneficial
  • Can give dose if intubated
• Enhanced elimination and antidotes n/a
• Disposition
  • Children can be observed at home unless symptomatic
  • If asymptomatic 6 hours post-ingestion, can discharge
  • If symptomatic observe until symptoms resolve (usually within 24 hours)

Newer agents

• Handy tips
  • If coma, consider alternative causes esp. carbamazepine, valproic acid, barbiturate

Lamotrigine rash

Last Updated on October 14, 2020 by Andrew Crofton